Diabetic neuropathy, diabetic cataracts and retinopathy, diabetic nephropathy, diabetic dermopathy and other diabetic microangiopathy have been known as chronic, difficult to treat diseases resulting from diabetes. Participation of a polyol metabolic system may be a cause of those diabetic complications.
Thus, when a hyperglycemic state results from diabetes, utilization of glucose via a polyol metabolic pathway increases several-fold compared with the normal state. Also, production of sorbitol by an aldose reductase is accelerated. It is presumed that, as a result thereof, intracellular sorbitol in peripheral nerves, retina, kidney, lens, artery and the like accumulates excessively. The excessive sorbitol accumulation leads to cell edema and hypofunction due to an abnormal osmotic pressure in the cells.
Accordingly, agents for inhibiting aldose reductase have been thought to be effective for the therapy and the prevention of diabetic complications and have been studied. However, conventional aldose reductase inhibitors are problematic because they strongly inhibit other enzymes which do not participate in the polyol metabolic pathway. For example, an aldehyde reductase may be undesirably inhibited by conventional aldose reductase inhibitors.
Under such circumstances, the present inventors have conducted a study to obtain inhibitors having a high enzyme selectivity toward aldose reductase which participates in the production of sorbitol with an object of providing therapy for and prevention of the above-mentioned diabetic complications. As a result, the present inventors have found that the carboxyalkyl heterocyclic derivatives of the present invention exhibit an excellent inhibitory action with a high enzyme selectivity to aldose reductase whereby the present invention has been achieved.